C-glycosides and preparation of thereof as antidiabetic agents

ABSTRACT

C-glycoside derivatives are disclosed, which are represented by the following formula (I) and its pharmaceutical acceptable salt, and which are useful for the treatment and/or prevention of diabetes and hypoglycemia.  
                 
 
     wherein: with the provisos that  
     R 1  is H, OH, lower alkyl, O-lower alkyl or  
                 
 
     ;  
     R 2  is H, —COO-lower alkyl,  
                 
 
     ;  
     R 5  is —CH 2 OH, —CH 2 OCO 2 -lower alkyl,  
                 
 
                 
 
     —CH 2 OSO 3 H, —COOH or —COONa;  
     wherein: A is  
                 
 
     (with the provisos that X is oxygen atom, nitrogen atom or sulfur atom R 3  is lower alkyl when is 1, R 3  is including —OH, —O-lower alkyl, . . . means saturated or unsaturated carbon bond;  
     m is O or 1;  
     n is 0, 1 or 2;  
     above mentioned-lower alkyl means C 1 -C 5 .)  
     or a pharmaceutical acceptable salt.

BACKGROUND OF THE INVENTION

[0001] 1. Field of the Invention

[0002] This invention regarding to new C-glycosides which are useful forthe treatment and/or prevention of diabetes and a pharmaceuticalcomposition containing these compounds as active ingredients. And thisinvention is also including the method of preparation of C-glycosides.

[0003] Current Technology

[0004] The anti-diabetic compounds which modulates energy valance andglucose levels in the body are required recently.

[0005] The Na⁺-glucose cotransporter (SGLT) located on the chorionicmembrane of the intestine and the kidney. Glucose is absorbed in theinvestive and the kidney mediated by SGLT.

[0006] The mechanism of inhibiting SGLT provides a novel approach totreat and/or prevent of diabetes. Because the inhibitory effect on SGLTmay be excrete extra glucose into urine and as a result, prevent chronichyperglycemia (Welch, C. A. et al., J.Natr., 1989,119(11)1698).

[0007] Phlorizin, O-glycosides, is reported as a specific inhibitor ofSGLT. And the series of O-glycosides are synthesized and reported theanti-diabetics activity of these compounds (Hanga, M.et al.,Chem.Pharm.Bull.1998,46(1)22, Tokukai 11-021243).

[0008] These series of O-glycosides, however, would be cleaved byglycosidase exsists in intestine when orally administrated.

[0009] And it is reported that phloretine, the aglycone of phlorizin,inhibit facilitated-type glucose transporter. For example, intravenouslyinjection of to rats result the reduction of glucose levels in rat brain(Stroke,1983,14,388).

[0010] To overcome the stability against glycosidases, acids and bases,the chemistry of C-glycosides which replace of internal oxygen atom tocarbone atom are reported (R. J. Linhardt.et al.,Tetrahedron, 1998,54,9913., D. E. Levy,The Chemistry of C-Glycosides.Pergamon;Oxford,1995., M. H. D. Postema, C-Glycoside Synthesis.CRC Press;BocaRaton.1995). However, it is not reported that C-glycosides has strongSGLT inhibitor, so far.

[0011] The Subject of the Invention

[0012] The present invention concerns metabolic and hydrolytic stableC-glycosides compounds. These C-glycosides excrete extra glucose intourine and show hypoglycemic activity and a pharmaceutical compositioncontaining these compounds as active ingredients. The present inventionalso includes the methods of preparing these C-glycosides compounds.

[0013] A Solution to the Invention

[0014] After elaborated to make C-glycosides which metabolic andhydrolytic stable for an anti-diabetics drug, the inventors found thatnew compounds as show general formula (I) had shown potent anti-diabeticactivities and fulfilled this invention. Namely, the invention is thecompounds as shown in general formula (I) and its pharmaceuticallyacceptable salts and a composition containing these compounds as activeingredients.

SUMMARY OF THE INVENTION

[0015] A novel C-glycosides and preparation of thereof as the treatmentand/or prevention agent of diabetes and the blood glucose lowering agentare provided.

DETAILED DESCRIPTION OF THE INVENTION

[0016] It is that the compounds as shown in general formula (I) and itspharmaceutically acceptable salts.

[0017] Namely, the invention is the compounds as shown in generalformula (I) and its pharmaceutically acceptable salts and a compositioncontaining those compounds as active ingredients.

[0018] wherein: with the provisos that

[0019] R₁ is H, OH, lower alkyl, O-lower alkyl or

[0020] R₂ is H, —COO-lower alkyl,

[0021] or

[0022] R₅ is —CH₂OH, —CH₂OCO₂-lower alkyl,

[0023] —CH₂OSO₃H, —COOH or —COONa;

[0024] wherein: A is

[0025] (with the provisos that X is oxygen atom, nitrogen atom or sulfuratom R₃ is lower alkyl when is 1, R₃ is including —OH, —O-lower alkyl, .. . means saturated or unsaturated carbon bond;

[0026] m is 0 or 1;

[0027] n is 0, 1 or 2;

[0028] above mentioned-lower alkyl means C₁-C₅.)

[0029] Enforcement of Invention

[0030] 48 compounds are exemplified as follow, but the invention is notlimited to these compounds. TABLE 1 Compound Structure mp (° C.)[α]D²³/(c, solv.) 1

135-136 −1.59(1, Py.) 2

226-228 −23.60(1, Py.) 3

>250 −24.80(0.5, Py.) 4

195-196 −40.19(1, Py.) 5

120-121 −35.80(1, Py.) 6

120-121 −10.80(1, Py.) 7

189-190 −42.00(0.1, Py.)

[0031] TABLE 2 Compound Structure mp (° C.) [α]D²³/(c, solv.) 8

228-229 +57.19(1, Py.) 9

137-138 −10.57 (0.643, CHCl₃) 10

181-183 −66.13(0.5, Py.) 11

239-242 −70.90(0.55, Py.) 12

183-185 −68.08(0.05, Py.) 13

236-239 −59.41(0.5, Py.) 14

226-228 −46(0.1, Py.)

[0032] TABLE 3 Compound Structure mp (° C.) [α]D²³/(c, solv.) 15

245-248 −28.0(0.1, Py.) 16

198-199 +1.19(1, Py.) 17

194-196 −44(0.1, Py.) 18

217-220 −60(0.1, Py.) 19

276-279 −72(0.1, Py.) 20

256-257 −86.00(1, Py.) 21

103-105 −2.39(0.5, Py.)

[0033] TABLE 4 Compound Structure mp (° C.) [α]D²³/(c, solv.) 22

226-228 −23.60(1, Py.) 23

112-113 −16.19(1, Py.) 24

89-90 −8.20(1, Py.) 25

175-176 −23.60(0.5, Py.) 26

191-192 +10.40(1, Py.) 27

118-119 −12.80 (0.5, CH₂Cl₂) 28

194-196 −52.0(0.1 , Py.)

[0034] TABLE 5 Compound Structure mp (° C.) [α]D²³/(c, solv.) 29

131-132 −15.59(1.0, Py.) 30

66-71 −20(0.1, Py.) 31

216-217 −44.80(1, Py.) 42

71-73 43

115-117 44

177-179 45

220

[0035] TABLE 6 Compound Structure mp (° C.) [α]D²³/(c, solv.) 46

77-79 47

113-114 −18.39 (0.5, MeOH) 48

 262 −11.60 (0.5, MeOH) 49

  128-128.5 +2.80 (1.0, MeOH) 50

>220 51

103-105 +4.79 (1, CHCl₃) 52

85-87 −8.00 (1, CHCl₃)

[0036] TABLE 7 Compound Structure mp (° C.) [α]D²³/(c, solv.) 53

58-60 −18.39 (1, CHCl₃) 54

227-228 −10.00 (1, CH₃OH) 55

80-83 +10.46 (1, CHCl₃) 56

amorphous −1.19 (1, CHCl₃) 57

118-120 −2.00 (1, CHCl₃) 58

199-201 −9.20 (1.0, MeOH)

[0037] Typical preparations of the compounds of general formula (I)according to the invention are shown, but the invention is not limitedto those examples.

[0038] The preparations of the compound of general formula (I).

[0039] (1) In case of R₂ is all hydrogen atoms.

[0040] The compounds can be obtained by means of the following diagram(wherein R₁, R_(4,) A₁, m, and n have the above-mentioned meaning): Thecompound of general formula (II) is converted to the compound of generalformula (I) by the aldol reaction with aldehyde compound of generalformula (IV), and followed by the catalytic hydrogenation of double bondof general formula I.

[0041] (2) In case of R₁ is —OH, R₂ is —H, or —COOCH₃.

[0042] The compounds can be obtained by means of the following reactiondiagrams (wherein A, m, and n have the above-mentioned meaning): Thephenolic hydroxy groups of the above-mentioned (I) is protected by allylgroup, and then reacted with methyl chloroformate in the presence ofbase to obtain the compound of general formula (V). After removal ofallyl groups of the compound (V) by the Pd catalyst, followed by thecatalytic hydrogenation of double bond, if necessary, the compound ofgeneral formula (VI) is obtained.

[0043] (3) In case of R₁ is —OH, R₂ is —H or

[0044] and R₅ is

[0045] The compound can be obtained by means of the following reactiondiagrams (wherein A and m have the above-mentioned meaning): Thecompound of general formula (I) is reacted with succinic anhydride inpyridine to obtain the compounds of general formula (XVII) and/or(XVIII).

[0046] (4) In case of R₂ is all hydrogen atoms, R₅ is CH₂OH and R₁ is

[0047] The compounds can be obtained by means of the following reactiondiagram (wherein A₁ and m have the above-mentioned meaning): Thephenolic hydroxy group of the compound of general formula (I) is reactedwith 4-bromomethyl-5-methyl-1,3-dioxolene in the presence of base, toobtain the compound of general formula (XIX).

[0048] The preparations of the compound of general formula (II).

[0049] (a) In case of m=0

[0050] The compound can be obtained by means of the following reactiondiagram (wherein R₁ and n have the above-mentioned meaning, X is halogen(Br, F, etc.), leaving group such as CF₃.CO.O—, and Bn is benzyl): Thecompound of general formula (VII) is reacted with benzene derivatives(VIII) in the presence of Lewis acid (e.g. BF₃.Et₂O, SnCl₄, AlCl₃,AgOSO₂CF₃ etc.) to synthesize the coupling compound (IX) (e.g.Jaramillo,C.et al.,Synthesis,1994,1)

[0051] And the compound of general formula (IX) can be also obtained byusing Grignards reaction of the compound (VII) with Grignards reagent(X) (e.g. Yokoyama,M.et al.,Synthesis,1998,409).

[0052] The process is shown in the following reaction diagram.

[0053] (b) In case of m=1

[0054] The compound can be obtained by means of the following reactiondiagram (wherein R₁ and n have the above-mentioned meaning): Thecompound of general formula (XII) as a starting material is synthesizedby the reaction of corresponding lactone (XI) with Tebbe reagent(Tebbe,F. N.,et al.,J.Am.Chem.Soc.,1978,100,361 1). The compound ofgeneral formula (XII) is hydroborated with 9-borabicyclo[3,3,1]nonane(9-BBN) followed by Suzuki coupling reaction with the compound ofgeneral formula (XIII) in the presence of palladium catalyst, to obtainthe compound of general formula (XIV) (e.g. Johnson,C. R.etal.,Synlett.,1997,1406).

[0055] And the compound can be obtained by means of the followingreaction diagram (wherein R₁, X, and n have the above-mentionedmeaning): 2,3,4,6-Tetra-O-benzyl-1-thio-β-D-glucopyranose (XX) isreacted with arylmethylhalide (XXI) to convert sulfide (XXII). Theoxidation of the compound (XXII) with OXONE® is led to sulfon (XXIII),and resulting compound (XXIII) is converted to olefin (XXIV) byRamberg-Bäcklund rearrangement reaction. The compound of general formula(XIV) can be aslo synthesized in large scale by the hydrogenation ofolefin (XXIV) in the present of palladium catalyst.

[0056] (c) The preparations of the compound of general formula (II)

[0057] The compounds can be obtained by means of the following reactiondiagram (wherein R₁ and n have the above-mentioned meaning): Thecompounds of general formula (XV) obtained as described above process(a) or (b), is catalytically reducted to debenzylated derivatives, andafter acetylation with A_(c2)O in pyridine, the compound of generalformula (XVI) is afforded.

[0058] The compound of general formula (II) (in case of R₄ is acetylgroup) is obtained by the Friedel-Crafts reaction of the compound ofgeneral formula (XVI). The compound of general formula (II) (in case ofR₄ is hydrogen atom) can be also obtained by the subsequentdeacetylation with NaOMe.

[0059] And in case of m=1, the compound of general formula (II) can bealso obtained as shown in the following reaction diagram (wherein R₁, Xand n have the above-mentioned meaning): When the Suzuki couplingreaction in above-mentioned process (b) is carried out, in stead ofarylhalide (XIII), the derivatives attached acetyl group (XXV) is usedto obtain the compound of general formula (XXVI).

[0060] Resulting compound can be converted to the compound of generalformula (III) or (II) by the debenzylation or followed by acetylation.

[0061] As pharmaceutical acceptable salts of a compound of generalformula (I), sodium salt, potassium salt and inorganic base arementioned.

[0062] In case of A₁ contains pyridine base, salts of inorganic andorganic acids are mentioned. As the salt of inorganic acid,hydrochloride and sulfate are mentioned. As the salt of organic acid,acetate, succinate and fumalate are mentioned.

[0063] A compound of general formula (I) can be used itself orformulated to pharmaceutical product such as powder, granule, tablet andcapsule by known pharmaceutical technology and can be orallyadministrable, It can be also administered not orally such as directadministration to rectal and in the form of injection. An effectivedosage of the compound is from 10 to 1000 mg once to several times a dayfor adults, through it may be adjusted depending an age, a body weightand symptoms.

[0064] PHARMACOLOGICAL EXPERIMENT

[0065] The pharmacological test of urinary glucose excretion in rat isdescribed that follow.

[0066] Measurement of Urinary Glucose Excretion in Rats

[0067] 20 mg of test compounds were dissolved in 10 mL saline containing20% dimethylsulufoxide.

[0068] Test compound (10 mg/5 mL/kg, i.p.) was administered twice an 8hr interval to male SD rats (6 weeks old, 3 animals/group). An equalvolume of vehicle was given to the control group. Urine was collectedfor 24 hr after first administration in metabolic cages.

[0069] The urine was centrifuged and urine volume was measured. Glucoseconcentration (mg/dl) was assayed using Glucose CII test Wako (Wako PureChemicals, Japan). The amounts of glucose excretion during 24 hr wascalculated from the following equation.

[0070] Glucose secretion (mg/24hr)=(A×B)/100

[0071] (A; the urine volume, B; the glucose concentration)

[0072] The result are shown in Table 8. TABLE 8 Urinary glucoseexcretion Compound Dose (mg/kg) (mg/24 hr) 1 10 4.1 3 10 241 4 10 289 510 228 6 10 8.9 22 10 124

EXAMPLE

[0073] The following Example are provided only for the purpose of thepreparation of the compound and not restrict the disclosed invention.The following compound 1-31 and 42-58 correspond to that of table 1-7.

Example 13-(Benzo[b]furan-5-yl)-1-(2′-β-D-glucopyranosylmethyl-6′-hydroxy-4′-methoxy)acrylophenone

[0074]

[0075] (a)1-(3,5-Dimethoxyphenylmethyl)-1-deoxy-2,3,4,6-tetra-O-benzyl-β-D-glucopyranose

[0076] To2,6-Anhydro-3,4,5,7-tetra-O-benzyl-1-deoxy-D-glucohept-1-enitol (2.0 g,XII), obtained from tetra benzylgluconolactone (XI) by Tebbe reaction,was added 9-BBN (0.5M in THF) at room temperature. After refluxing for 7hr, the reaction mixture was cooled to room temperature and 3M K₃PO₄(3.3 mL) was added. This was followed by the addition of1,3-dimethoxyiodobenzene (1.2 g), and PdCl₂ (dppf) (160 mg). Resultingsolution was stirred at room temperature for 3 hr. The reaction mixturewas poured into Et₂O (30 mL) and washed with brine. Organic layer wasdried over Na₂SO₄. Filtration and obtained residue was followed bychromatography on silicagel (10:1 n-hexane/EtOAc) to give the compound33 in 92% yield

[0077] Mass (m/e): 675(M⁺+1),583,475,369,91(BP)

[0078] IR (cm⁻¹): 3022,2908,1455,1413,1389

[0079]¹H-NMR (CDCl₃):2.75(dd,1H,J=14.0,9.0Hz),3.17(d,1H,J=9.0Hz),3.37(m, 2H),3.52(m,1H),3.60˜3.74(m,4H),3.70(S,6H),4.52˜4.70(m,4H),4.82˜4.96(m,4H),6.35(S,1H),6.42(S,2H),7.20˜7.38(m,25H).

[0080] (i)1-[(3,5-Dimethoxyphenyl)methylthio]-1-deoxy-2,3,4,6-tetra-O-benzyl-β-D-glucopyranose(XXII)

[0081] To a mixture of 2,3,4,6-tetra-O-benzyl-1-thio-β-D-glucopyranose(XX, 5.43 g) in acetone (40 mL), was added 3,5-dimethoxy benzylchloride(1.82 g) and a solution of K₂CO₃ (1.35 g) in H₂O (10 mL). The mixturewas heated under reflux for 2 hr. After cooling, solvent was removed.The residue was dissolved in H₂O and extracted with AcOEt (2×30 mL). Theorganic layer was washed with Brine, dried over Na₂SO₄ and evaporated.The crude product was purified by silicagel column chromatography (8:1n-hexane/AcOEt) to give the compound (XXII) in 90.5% yield.

[0082] IR (cm⁻¹):3022,2854,1734,1596,1494,1455,1431,1398,1350,1320,1293,1203, 1149,1062,909,831,735,696

[0083]¹H-NMR (CDCl₃) δ: 3.71 (s,6H)3.39˜3.98(m,8H),4.30(d,1H,J=9.8Hz),4.53-4.89(m,8H),6.33(t,1H, J=2.0 Hz),6.51(d,2H, J=2.5Hz),7.15-7.37(m,20H).

[0084] (ii) 1-[(3,5-Dimethoxyphenyl)methyl]sulfonyl-1-deoxy-2,3,4,6-tetra-O-benzyl-β-D-glucopyranose (XXIII)

[0085] To a mixture of 5.25 g of the compound obtained as describedabove (i) in acetone (45 mL), were added H₂O (15 mL) and OXONE® (13.7g). The mixture was stirred at room temperature for 24 hr. Solvent wasremoved. The residue was dissolved in H₂O and extracted with AcOEt (2×50mL). The organic layer was washed with brine, dried over Na₂SO₄, andevaporated. The crude product was purified by silicagel columnchromatography (4:1 n-hexane/AcOEt) to give the compound (XXIII) in79.5% yield.

[0086] IR(cm⁻¹):3058,3022,2914,1731,1599,1494,1455,1431,1401,1329,1269,1242,1206,1152,1092,1026,996,933,882,837,738,696,540

[0087]¹H-NMR (CDCl₃) δ: 3.51-4.09(m,6H),3.71 (s,6H),4.22(d,1H,J=9.3Hz),4.51-4.98(m,8H),4.57(s,2H),6.42(m,1H),6.63(d,2H,J=2.4Hz),7.15-7.34(m,20H)

[0088] (iii)1-[(3,5-Dimethoxyphenyl)methylene]-1-deoxy-2,3,4,6-tetra-O-benzyl-β-D-glucopyranose(XXIV)

[0089] To a mixture of 1.42 g of the compound obtained as describedabove (ii) in CCl₄ (15 mL) and 2-methyl-2-propanol (15 mL), were addedH₂O (1.5 mL) and KOH (7 g). The mixture was heated under reflux for 1hr. After cooling, the mixture was poured into ice-water, and extractedwith AcOEt (2×20 mL). Organic layer was washed with H₂O (1×10 mL), brine(1×10 mL), dried over Na₂SO₄, and evaporated. The crude product waspurified by silicagel column chromatography (4:1 n-hexane/AcOEt) to givethe compound (XXIV) in 63.7% yield.

[0090] Mass (m/e): 672(M⁺),247,181,135,91(BP),51

[0091] IR (cm⁻¹):3058,3022,2920,2860,1656,1593,1494,14521425,1359,1329,1299,1257,1203,1149,1065,912,846,735

[0092]¹H-NMR (CDCl₃) δ:3.64(s,3H),3.73(s,3H),3.61-4.79(m,14H),5.60-6.90(m, 4H),7.05-7.37(m,20H)

[0093] (iv)1-(3,5-Dimethoxyphenylmethyl)-1-deoxy-2,3,4,6-tetra-O-benzyl-β-D-glucopyranose(XIV)

[0094] To a mixture of 0.76 g of the compound obtained as describedabove (iii) in MeOH (10 mL), was added 5% Pd-C (0.2 g). After stirringunder hydrogen at room temperature for 30 min, the mixture was filteredand evaporated. The residue was purified by silicagel columnchromatography (8:1 n-hexane/AcOEt) to give the compound (XIV) in 56.8%yield.

[0095] Mass (m/e): 675(M⁺+1),583,475,369,91(BP)

[0096] IR (cm⁻¹): 3022,2908,1455,1413,1389

[0097]¹H-NMR (CDCl₃) δ: 2.65-3.11(dABq,2H,J=14.2Hz),3.32-3.74(m,7H),3.69(s, 6H),4.49-4.95(m,8H),6.30(t,1H,J=2.0Hz),6.46(d,2H,J=2.4 Hz),7.18-7.37(n, 20H)

[0098] (b) 1-(3,5-Dimethoxyphenyl)-1-deoxy-β-D-glucopyranose (Compound34)

[0099] To a mixture of 3.0 g of the compound obtained as described above(a) in MeOH, was added 5% Pd-C (1.0 g). After stirring under hydrogen atroom temperature for 15 min, the mixture was filtered off over a Celite®and evaporated to give the compound 34 in quantitative yield.

[0100]¹H-NMR (DMSO:CDCl₃=2:1):2.57-3.28(m,7H),3.46-3.69(dABq,2H),3.72(s, 6H),6.26(t,1H),6.47(d,2H)

[0101] (c)1-(3,5-Dimethoxyphenylmethyl)-1-deoxy-(2,3,4,6-tetra-O-acetyl)-β-D-glucopyranose(Compound 35)

[0102] To a mixture of 1.0 g of the compound obtained as described above(b) in pyridine (10 mL) was added acetic anhydride (5 mL) at 0° C. Themixture was stirred at room temperature for 12 hr and poured into AcOEt(30 mL). The organic layer was washed with brine, dried over Na₂SO₄, andevaporated. The residue was purified by silicagel column chromatography(1:1 n-hexane/AcOEt) to give the compound 35 in 81% yield. mp=103-105°C.

[0103] Mass (m/e): 482(M⁺),303,247,217,189,152(BP),109,81,51

[0104] IR (cm⁻¹): 1737, 1596, 1368, 1242

[0105]¹H-NMR (CDCl₃):1.99,2.00,2.02,2.03(12H),2.74˜2.76(m,2H),3.78(S,6H),3.58˜5.19(m,7H),6.33˜6.36(m,3H)

[0106] (d)2-Hydroxy-4-methoxy-6-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosylmethyl)-acetophenone

[0107] To a mixture of 1.2 g of the compound obtained as described above(c) in diethylether (20 mL), was dropwised a solution of AlCl₃ (3.5 g)in Et₂O (20 mL) at 0° C. After stirring at room temperature for 12 hr,the mixture was poured into diluted hydrochloric acid, and extractedwith methylene chloride. Organic layer was washed with satd. NaHCO₃ aq.and brine, dried over Na₂SO₄, and evaporated. The crude product waspurified by silicagel column chromatography (4:1 n-hexane/AcOEt) to givethe compound 36 in 58% yield (742 mg). mp=159-160° C.

[0108] Mass (m/e):510(M⁺),474,417,373,331,275,233,205,169,139,109(BP),81,47

[0109] IR (cm⁻¹): 3400,2914,1752,1686,1605,1371,1218,1173

[0110]¹H-NMR (CDCl₃):2.00˜2.03(m,12H),2.65(S,3H),3.61˜3.68(m,2H),3.90(S,3H),4.06˜5.21(m,7H),6.23(S,1H),6.44(S,1H),13.27(S,1H)

[0111] (e)3-(Benzo[b,]furan-5-yl)-1-(2′-β-D-glucopyranosylmethyl-6′-hydroxy-4′-methoxy)acrylophenone (Compound1)

[0112] To a mixture of 203 mg of the compound obtained as discribedabove (d) and 5-benzofuranaldehyde (70 mg) in EtOH (2 mL), was added 0.4mL of 50% KOH at 0° C. After stirring at room temperature for 12 hr, themixture was adjusted to ca pH 4 with 10% HCl, and extracted with ethylacetate. The organic layer was washed with satd. NaHCO₃ and brine, driedover Na₂SO₄, and evaporated. The crude product was purified by silicagelcolumn chromatography (9:1 chloroform/MeOH) to give the compound 1 (102mg) in 55% yield. mp=135-136° C. [α]²³D=−1.59 (C=1, Py.)

[0113] Mass (m/e):470(M⁺),434,403,350,319,290,261,219,191,164,131(BP),91,60

[0114] IR (cm⁻¹): 3370,2914,1605,1440,1263,1197,1155,1086,1026

[0115]¹H-NMR (CDCl₃): 2.63˜2.65,2.95˜3.00(m,3H),3.07˜3.78(m,6H),3.81(S,3H) 6.40,6.48(ABq,2H,J=2.4 Hz),6.79(S,1H),7.13˜7.73(ABq,2H,J=15.6 Hz),7.49˜7.57(ABq,2H,J=8.3 Hz),7.65(S,1H),7.81(S,1H),10.02(brs,1H)

Example 23-(Benzo[b]furan-5-yl)-2′-β-D-glucopyranosylmethyl-6′-hydroxy-4′-methoxypropiophenone(Compound 21)

[0116]

[0117] To a mixture of 0.13 g of the compound obtained as describedabove (e) of Example 1 in 1:1 THF-MeOH (10 mL), was added 0.1 g of 5%Pd-C. After stirring under hydrogen at room temperature for 30 min, themixture was filtered off over a Celite® and evaporated. The crudeproduct was purified by silicagel column chromatography (10:1chloroform/MeOH) to give the compound 21 (80 mg) in 61% yield.mp=103-105° C. [α]²³D=−2.39 (C=0.5, Py.)

[0118] Mass (m/e): 472(M⁺),434,374,319,291,243,205,177,131(BP),91,57

[0119] IR (cm⁻¹): 3400,2914,1605,1443,1266,1197,1104

[0120]¹H-NMR (CDCl_(3:)DMSO=1:2):3.04˜3.13(m,2H),3.83(S,3H),3.34˜5.60(m, 11H),6.42˜7.83(m,7H)

Reference 12-(β-D-glucopyranosylmethyl)-6-hydroxy-4-methoxy-acetophenone (Compound32)

[0121]

[0122] To a mixture of 336 mg of the compound 36 obtained as describedabove (d) of Example 1 in methanol (5 mL), was added 28 mg of Sodiummethoxide at 0° C. After stirring at room temperature for 1 hr. Ionexchange resin (ca 1 g) was added and stirred for 10 min, filtered, andevaporated. The residue was purified by silicagel column chromatography(10:1 chloroform/MeOH) to give the compound 32 (225 mg) in 99% yield.The compound 32 was also used as a material, when the compound 1 and 2were synthesized. mp=98-99° C. [α]²³D=−2.80 (C=1.0, Py.)

[0123] Mass (m/e): 342(M⁺),324,306,221,191(BP),165,137,115,91,69,51

[0124] IR (cm⁻¹): 3388,1608,1356,1263,1200,1155,1080

[0125]¹H-NMR (CDCl_(3:)DMSO=1:2): 2.46(S,3H),2.55˜2.61(m,1H),2.91(t,1H,J=9.3,8.8 Hz),2.98˜3.19(m,5H),3.42˜3.65(dABq,2H,J=11 Hz),3.72(S,3H),4.14(brs,1H),4.79,4.83(brs,2H),4.95(brs,1H),6.27(d,1H,J=2.0 Hz),6.41(d,1H,J=2.4 Hz),9.86(S,1H)

Reference 22,4-Dimethoxy-5-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)acetophenone(Compound 37)

[0126]

[0127] Friedel-Crafts reaction of2,3,4,6-tetra-O-acetyl-1-(2,4-dimethoxyphenyl)-1-deoxy-β-D-glucopyranose(17.8 g), obtained by widely known method (R.Tschescheetal,etal.,Liebigs Ann.Chem.902˜907,1982), with aluminum chloride and aceticanhydride gave the reported compound 38 in 57% yield (10.78 g). And thecompound 37 was also obtained in 10.1% yield (1.95 g) as a by-product.The compound 37 and 38 were used as a material to synthesize thecompound 23 and 3, respectively. The measured value was shown below.

[0128] Mass (m/e): 510(M⁺),317,275(BP),209,179,139,97,69

[0129] IR (cm⁻¹): 3460,2939,1746,1653,1605,1578,1500,1443,1368

[0130]¹H-NMR (CDCl₃):1.77(S,3H),2.01(S,3H),2.05(S,3H),2.08(S,3H),2.56(S,3H), 3.78˜3.81(m,1H),3.92(S,3H),3.93(S,3H),4.12˜4.26(dABq,2H,J=12.2 Hz), 4.71(d,1H,J=10.3Hz),5.21(t,1H,J=9.6 Hz),5.32(t,1H,J=9.6 Hz),5.44 (t,1H, J=10.3Hz),6.39(S,1H),7.88(S,1H)

Example 33-(Benzo[b]furan-5-yl)-3′-β-D-glucopyranosyl-6′-hydroxy-4′-methoxyacrylophenone(Compound3)

[0131]

[0132] To a mixture of 2.0 g of the compound 38 obtained by widely kownmethod (R.Tschesche,et al.,Liebigs Ann.Chem.902˜907,1982) and 0.71 g of5-benzofuranaldehyde in ethanol (25 mL), was added 50% KOH at 0° C. Themixture was stirred at room tempareture for 12 hr. Then, to the mixturewas added water, and washed with chloroform. Aqueous layer was adjustedto pH 3 with 10% hydrochloric acid, and extracted with chloroform. Thischloroform layer was washed with brine, dried over Na₂SO₄, andevaporated. The residue was purified by silicagel column chromatography(10:1 chloroform/MeOH) to give the compound 3 (1.15 g) in 63% yield.mp>250° C. [α]D=−24.80 (C=0.5, Py.)

[0133] Mass (m/e): 456(M⁺),259,195,145,177,66(BP)

[0134] IR(cm⁻¹): 3376,2908,1632,1566,1497,1446,1368,1281,1260

[0135]¹H-NMR (CDCl_(3:)DMSO=1:2):3.22˜3.57(m,4H),3.73(d,2H),3.88(s,3H),4.48(d,1H),6.51(s,1H),6.98(d,1H),7.64(d,1H),7.87˜8.09(m,3H),8.15(s,1H),8.16(d,1H),13.61(s,1H)

Example 43-(Benzo[b]furan-5-yl)-3′-β-D-glucopyranosyl-4′-methoxy-6′-(2-propen-1-yl)oxy-acrylophenone(Compound 39)

[0136]

[0137] To a solution of the compound 3 (1.15 g) in acetone (20 mL) wereadded potassium carbonate (0.97 g) and allylbromide (0.3 mL), thereaction mixture was heated under reflux for 12 hr. The reaction mixturewas poured into ice-water, and extracted with chloroform. Organic layerwas washed with brine, dried over Na₂SO₄, and concentrated. The crudeproduct was purified by silicagel column chromatography (20:1chloroform/MeOH) to give the compound 39 (1.04 g) in 83% yield.mp=139-140° C. [α]²³D=−14.60 (C=1, Py.)

[0138] Mass (m/e):497(M⁺+1),435,358,311,283,253,207,177(BP),147,119,92,65

[0139] IR (cm⁻¹): 3400,2896,1608,1575,1443,1314,1260,1200,1122,1083

[0140]¹H-NMR (CDCl_(3:)CD₃OD=9:1):3.45˜3.47(m,1H),3.54˜3.65(m,3H),3.73˜3.89 (dABq,2H,J=12.2Hz),3.93(S,3H),4.68˜4.72(m,3H),5.31(dd,1H,J=10.3, 10.7Hz),5.48(dd,1H,J=17.1,17.6 Hz),6.06˜6.13(m,1H),6.54(S,1H),6.82(S,1H),7.52(d,1H,J=8.4 Hz),7.59(d,1H,J=8.0Hz),7.64(S,1H),7.69(S,1H),7.80˜7.84(S+m,3H)

Example 53-(Benzo[b]furan-5-yl)-3′-(6-O-methoxycarbonyl-β-D-glucopyranosyl)-4′-methoxy-6′-(2-propen-1-yl)oxy-acrylophenone(Compound 40)

[0141]

[0142] To a solution of compound 39 (0.97 g) and 2,4,6-collidine (2.6mL) in methylene chloride (5 mL) was dropwised a solution of methylchloroformate (0.18 mL) in methylene chloride, the reaction mixture wasstirred at room temperature for 2 hr. The reaction mixture was pouredinto diluted hydrochloric acid, and extracted with ethyl acetate.Organic layer was washed with satd. NaHCO₃ and brine, dried over Na₂SO₄,and concentrated. The crude product was purified by silicagel columnchromatography (20:1 chloroform/MeOH) to give the compound 40 (0.77 g)in 71% yield. mp=137-138° C. [α]²³D=−4.79 (C=1, Py.)

[0143] Mass (m/e):554(M⁺),505,478,446,404,361,310,282,243,213(BP),183,156,124

[0144] IR (cm⁻¹): 3400,2908,1743,1608,1575,1503,1443,1263,1197,1125

[0145]¹H-NMR (CDCl₃): 3.07(d,1H,J=3.6Hz),3.46,3.50(brs,2H),3.63˜3.85(m,4H),3.76(S,3H),3.90(S,3H),4.43˜4.47(ABq,2H),4.65˜4.66(m,2H),4.71(d,1H, J=9.8Hz),5.28(dd,1H,J=10.7,10.2 Hz),5.45(dd,1H,J=17.1 Hz),6.02˜6.09(m,1H),6.48(S,1H),6.75,7.65(d,2H,J=2.4 Hz),7.48˜7.58(ABq,2H,J=8.4 Hz),7.57(S,1H),7.76,7.81(d,2H,J=1.2 Hz),7.85(S,1H)

Example 63-(Benzo[b]furan-5-yl)-3′-(6-O-methoxycarbonyl-β-D-glucopyranosyl)-6′-hydroxy-4′-methoxy-acrylophenone(Compound 4)

[0146]

[0147] To a solution of the compound 40 (0.35 g) in acetonitrile (3 mL)was added PdCl₂ (Ph₃P)₂ (14 mg) and ammonium formate (0.24 g), thereaction mixture was heated under reflux for 12 hr, filtered, andconcentrated. The crude product was purified by silicagel columnchromatography (40:1 chloroform/MeOH) to give the compound 4 (0.13 g) in39.3% yield. mp=195-196° C. [α]²³D=−40.19 (C=1, Py.)

[0148] Mass (m/e): 514(Nr),438,378,336,307,257,219,163(BP),131,74

[0149] IR (cm⁻¹): 3400,2902,1746,1629,1560,1440,1371,1260

[0150]¹H-NMR (DMSO:CDCl₃=2:1):3.37˜3.39(m,1H),3.47˜3.51(m,1H),3.65(S,3H),3.75˜3.79(ABq,1H),3.88(S,3H),4.12˜4.17(m,1H),4.40˜4.47(m,2H),4.83(d,1H,J=5.4 Hz),5.07(d,2H,J=3.4 Hz),5.19(d,2H,J=4.4 Hz),6.53(S,1H),6.99(S,2H),8.07(S,2H),7.65(d,2H,J=8.3 Hz),7.90(d,2H,J=8.8 Hz),7.97(S,1H),8.18(S,1H),13.61(S,1H)

Example 7 3-(Benzo[b]furan-5-yl)-3′-(6-O-methoxycarbonyl-β-D-glucopyranosyl)-6′-hydroxy-4′-methoxy-propiopenone(Compound 5)

[0151]

[0152] To a solution of the compound 4 (114 mg) in MeOH-THF (1:1, 2 mL)was added 5% Pd-C (50 mg), the reaction mixture was stirred underhydrogen at room temperature for 15 min. The reaction mixture wasfiltered and concentrated. The crude product was purified by silicagelcolumn chromatography (40:1 chloroform/MeOH) to give the compound 5 (88mg) in 77% yield. mp=120-121° C. [α]²³D=−35.80 (C=1, Py.)

[0153] Mass (m/e): 516(M⁺),403,348,307,277,227,193,163,120,91,62(BP)

[0154] IR (cm⁻¹): 3394,2908,1743,1629,1494,1443,1337,175,1206

[0155]¹H-NMR (CDCl₃): 2.12(d,1H,J=3.9 Hz),2.88(d,1H,J=2.0Hz),2.96˜3.00(m,2H),3.15˜3.24(m,3H),3.48˜3.68(m,4H),3.75(S,3H),3.87(S,3H),4.40˜4.51(dABq,2H),4.53˜4.62(m,2H),4.63(d,1H),6.44(S,1H),6.72(d,1H,J=7.8 Hz),6.99(d,1H,J=6.8 Hz),7.09(S,1H),7.68(S,1H),12.86(S,1H)

Reference 31-(4-methoxy-2-methylphenyl)-1-deoxy-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranose(Compound 41)

[0156]

[0157] To a solution of 2,3,4,6-tetra-O-benzyl-D-glucopyranosyl fluoride(13.6 g) in THF (50 mL) was dropwised a solution of4-methoxy-2-methylphenyl magnesium bromide in THF (prepared frommagnesium (6 g) and 2-bromo-5-methoxytoluene (50 g)) at 0° C. Thereaction mixture was stirred at room temperature for 12 hr, and pouredinto ice-water, then neutralized with 10% hydrochloric acid, andextracted with ethyl acetate. Organic layer was washed with satd. NaHCO₃and brine, dried over Na₂SO₄, and concentrated. The residue was purifiedby silicagel column chromatography (8:1 n-hexane/ethyl acetate) to givethe compound 41 (13.1 g) in 81% yield. The compound 41 was used as amaterial to synthesize the compound 9 and 27.

[0158] Mass (m/e): 644(M⁺),553,433,341,293,241,181(BP)135,92,50

[0159] IR (cm⁻¹) (Neat):3052,3016,2890,2854,1608,1578,1497,1452,1393cm−1

[0160]¹H-NMR (CDCl₃):2.37(s,3H),3.52˜3.85(m,6H),3.81(s,3H),4.36(d,1H),4.46˜4.96(m,8H),6.71(s,1H),6.78(d,1H)6.92˜7.33(m,20H),7.39(d,1H)

Example 8-23

[0161] According to a similar procedure described in Example 3, thecompound 2, 6-20 were synthesized via aldol reaction, using acetophenonederivatives as a starting materials.

Example 24-34

[0162] According to a similar procedure described in Example 2, thecompound 21-31 were synthesized via catalytic hydrogenation of doublebond of enone derivatives.

Example 353-[({6-[5-(3-Benzo[b]furan-5-ylpropanoyl)-4-hydroxy-2-methoxyphenyl]-1-deoxy-β-D-glucopyranos-1-yl}carbonyl]propionicacid (Compound 47)

[0163]

[0164] To a solution of the compound 22 (330 mg) in pyridine (5 mL) wasadded succinic anhydride (144 mg), the reaction mixture was stirred atroom tempareture for 12 hr. The reaction mixture was poured intoice-water, and extracted with ethyl acetate. Organic layer was washedwith brine, dried over Na₂SO₄, and concentrated. The crude product waspurified by silicagel column chromatography (20:1 chloroform/MeOH) togive the desired compound (0.14 g) in 34.8% yield. mp=113-114° C.,[α]²³D=−18.39 (C=0.5, MeOH)

[0165] Mass (m/e,ESI): 557(M−H)⁻

[0166]¹H-NMR (CDCl₃)δ: 2.67(m,4H),2.96(t,2H,J=7.8Hz),3.10-5.07(m,12H),3.83(s,3H),6.42(s,1H),6.72(s,1H),6.96-7.73(m,5H),12.87(s,1H)

Example 36 3-(Benzo[b]furan-5-yl)-3′-(6-sulfonicacid-β-D-glucopyranosyl)-4′-methoxy-6′-hydroxyacrylophen one (Compound44)

[0167]

[0168] To a solution of the compound 3 (60 mg) in DMF (2 mL) was addedDMF SO₃ complex (403 mg), and then stirred at room temperature for 2 hr.To the reaction mixture was added EtOH-AcOEt (4:1), and stirredwhereupon the desired product (38 mg) precipitated as red crystals in54% yield. mp-177-179° C.

[0169] Mass(m/e,ESI): 537(M+H)⁺

[0170] IR (cm⁻¹)3382,1637,1563,1467,1368,1257,1107,1086,993

[0171]¹H-NMR (DMSO+CD₃OD) δ: 3.36(m,1H),3.46(m,2H),3.65(dd,1H,J=5.7 Hz),3.67-3.83(m,2H),3.95(s,3H),6.63(s,1H),7.07(d,1H,J=2.0 Hz),7.73(d,1H,J=8.8 Hz),7.97(dd,1H,J=8.8 Hz,2.0 Hz),8.01-8.10(m,3H),8.23(d,2H,J=10.7Hz)

Example 37 3-(Benzo[b]furan-5-yl)-3′-(6-carboxysodiumsalt-β-D-glucopyranosyl)4′-methoxy-6′-hydroxy-acrylophenone (Compound43)

[0172]

[0173] To a solution of the compound 3 (100 mg) in acetonitrile (3 mL)was TEMPO (4 mg) and KBr (4 mg) at room temperature, and then addedsatd. NaHCO₃ aq. (3 mL) and NaOCl (3 mL). The reaction mixture wasstirred for 30 min, and diluted AcOEt (50 mL), neutralized with 10% HCl.Organic layer was dried over Na₂SO₄, and concentrated. The residue waspurified by silicagel column chromatography (1:10 MeOH/CHCl₃) to givecarboxylic acid (63 mg) in 61% yield. To a solution of this carboxylicacid (63 mg) in acetone (1 mL) was added 1 equiv. of NaOH (5 mg), andstirred for 30 min, evaporated to give 43 mg of desired compound.mp=115-117° C.

[0174] Mass(m/e,ESI): 492(M+H)⁺

[0175] IR (cm⁻¹)3364,1608,1548,1446,1257,1152,108,735,594

[0176]¹H-NMR (D₂O) δ:3.30(m,1H),3.54(m,3H),3.83(s,3H),4.55(m,1H),6.27(s,1H),6.95(s,1H)7.60-8.10(m,7H)

Example 384-({2-(3-Benzo[b]furan-5-ylpropanoyl)-5-methoxy-4-(β-D-glucopyranosyl)phenoxy} methyl)-5-methy-1,3-dioxolene-2-one (compound 49)

[0177]

[0178] To a solution of the compound 22 (0.25 g) in DMF (3mL) was addedpotassium carbonate (75 mg) and4-bromomethyl-5-methyl-1,3-dioxolen-2-one (0.13 g), the reaction mixturewas stirred at room temperature for 3 hr. The reaction mixture waspoured into ice-water and extracted with ethyl acetate. Organic layerwas washed with brine, dried over Na₂SO₄, and concentrated. The crudeproduct was purified by silicagel column chromatography (20:1chloroform/MeOH) to give 42 mg of the desired compound.

[0179] mp=128-128.5° C., [α]²³D=+2.80 (C=1.0, MeOH)

[0180] Mass(m/e,ESI): 539(M+Na)⁺

[0181]¹H-NMR (CDCl₃) δ: 2.05(s,3H),2.90(t,2H,J=7.8Hz),3.07-3.89(m,9H),3.91 (s,3H),4.54-4.69(ABq,2H),6.47(s,1H),6.73(s,1H),6.80-7.10(ABq,2H),7.39(s,1H),7.59(s,1H),7.85(s,1H)

Example 39

[0182] According to a similar procedure described in Example 35, thecompound 46 was obtained from the compound 3, using 4 equiv. of succinicanhydride.

Example 40

[0183] According to a similar procedure described in Example 35, thecompound 42 was synthesized from the compound 3 as a starting materials.

Example 41-43

[0184] According to a similar procedure described in Example 37, thecompound 45, 48 and 50 were synthesized from the correspondingcarboxylic acid.

Example 443-(Benzo[b]furan-5-yl)-1-[6-hydroxy-4-methyl-2-{(β-D-glucopyranos-1-yl)methyl}]propiophenone

[0185]

[0186] (a)1-[6-Hydroxy-4-methyl-2-{(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)methyl}]acetophenone

[0187] Instead of 1,3-dimethoxy-5-iodebenzene,2-bromo-6-hydroxy-4-methylacetophenone was reacted in a similar manner described in Example 1 toobtain the compound 59 in 53% yield.

[0188] Mass (m/e,ESI): 709(M+Na)⁺,687(M+H)⁺

[0189] IR (cm⁻¹): 2914,1359,1083,750,696

[0190]¹H-NMR (CDCl₃) δ:2.21(s,3H),2.59(s,3H),2.97-3.01(m,1H),3.22-3.67(m,8H),4.42-5.00(m,8H),6.68(s,1H),6.67(s,1H),7.18-7.38(m,20H),11.7(s,1H)

[0191] (b)3-(Benzo[b]furan-5-yl)-1-[6-hydroxy-methyl-2-{(2,3,4,6-tetra-O-benzyl)-β-D-glucopyranosylmethyl}]acrylophenone (Compound 60)

[0192] To a mixture of 9.89 g of the compound obtained from the abovementioned step (a) and 2.31 g of 5-benzofuranaldehyde in EtOH (140 mg),was added 50% KOH (17 mL) at 0° C. The mixture was stirred at roomtempareture for 40 hr. To this mixture was added water and extractedwith ethyl acetate. Organic layer was washed with brine, dried overNa₂SO₄, and evaporated. The crude product was purified by silicagelcolumn chromatography (10:1 n-hexane/AcOEt) to give the compound 60 (7.2g) in 61% yield.

[0193] Mass (m/e,ESI): 837(M+Na)⁺,815(M+H)⁺,849(M+Cl),813(M−H)⁻

[0194] IR (cm⁻¹): 1732,1628,1578,1240,1100,760

[0195]¹H-NMR (CDCl₃) δ:2.27(s,3H),3.07-3.80(m,9H),4.40-4.94(m,8H),6.70(s,1H),6.73(s,1H),6.76(dd,1H,J=1.0 Hz,2.0 Hz),7.14-7.81(m,26H),10.8(s,1H)

[0196] (c)3-(Benzo[b]furan-5-yl)-1-[6-hydroxy-4-methyl-2-{(β-D-glucopyranos-1-yl)methyl}]acrylophenone

[0197] To a mixture of 7.2 g of the compound obtained from the abovementioned step (b) in CH₂Cl₂ (86 mL), was added BBr₃ (1.0M CH₂Cl₂solution,53 mL) at −78° C. The mixture was stirred for 2 hr at −78°C.→room temperature. The reaction mixture was poured into ice-water (200mL) and extracted with ethyl acetate. Organic layer was washed withwater, satd. NaHCO₃ and brine, dried over Na₂SO₄, and concentrated. Thecrude product was purified by silicagel column chromatography (20:1chloroform/MeOH) to give the compound 51 (3.0 g) in 76% yield.

[0198] Mass (m/e,ESI): 455(M+H)⁺,453(M−H)⁻

[0199] IR (cm⁻¹): 3394,3004,2908,1575,1443,1263,1215,1089

[0200]¹H-NMR (CDCl₃) δ: 2.27(s,3H),2.89-3.75(m,13H),6.68(d,2H,J=12.7 Hz)6.77(d,1H,J=1.5 Hz),7.08(d,1H,J=16.1 Hz),7.47-7.53(m,2H),7.63-7.66(m,2H),7.77(s,1H),8.68(bs,1H)

[0201] (d)3-(Benzo[b]furan-5-yl)-1-[6-hydroxy-4-methyl-2-1{(β-D-glucopyranos-1-yl)methyl}]propiophenone

[0202] To a mixture of 3.0 g of the compound obtained from the abovementioned step (c) in MeOH (100 mL), were added DMAP (0.81 g) and 5%Pt-C (0.30 g). After stirring under hydrogen at room temperature for 20hr. The mixture was filtered and evaporated. The residue was purified bysilicagel column chromatography (10:1 chloroform/MeOH) to give thecompound 52 (2.5 g) in 83% yield.

[0203] Mass (m/e,ESI): 456(M⁺),438,305,261,175,131(BP),91

[0204] IR (cm⁻¹): 3394,2908,1614,1083,1032

[0205]¹H-NMR (CDCl₃) δ: 2.24(s,3H),2.47-3.73(m,15H),6.62(d,1H,J=2.2Hz),6.68(s, 1H),7.08(d,1H,J=8.8Hz),7.37-7.57(m,2H),7.57(s,1H),8.83(bs,1H)

Example 45 3-Benzo [b]furan-5-yl-1-(6-hydroxy-4-methyl-2-{[6-methoxycarbonyl-β-D-glucopyranos-1-yl]methyl})propiophenone(Compound 53)

[0206]

[0207] According to a similar procedure described in Example 4, 5 and 6,the compound 53 was synthesized from the compound 52 which obtained asdescribed above Example 44.

Example 461-[2,4-Dihydroxy-6-{(β-D-glicopyranosyl)methyl}phenyl]-3-(4-hydroxyphenyl)propan-1-one(Compound 54)

[0208]

[0209] Instead of1-[6-hydroxy-4-methyl-2-{(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)methyl}]acetophenone (Compound 59) and5-benzofuranaldehyde,1-[2,4-dihydroxy-6-{(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)methyl}]acetophenoneand 4-benzyloxybenzaldehyde were reacted in a similar manner describedin Example 44 step (b), to obtained enone derivatives (1.2 g). To amixture of this compound in methanol (20 mL), was added 1.2 g of 5%Pd-C. After stirring under hydrogen at room temperature for 6 hr, thereaction mixture was filtered and evaporated. The residue was purifiedby silicagel column chromatography (4:1 chloroform/MeOH) to give thecompound 54 (0.52 g) in 88% yield. mpp=227-228° C., [α]²³D=−10.80(C=1.0, MeOH)

[0210] Mass (m/e,ESI): 457(M+Na)⁺,469(M+Cl)⁻,433(M−H)⁻

[0211] IR (cm⁻¹): 3358,2914,1605,1510,1460,1365,1260,1160,1100,840

[0212]¹H-NMR (DMSO:CDCl₃=2:1) δ: 2.43(dABq,1H,J=15.1 Hz),2.75(t,2H,J=7.6Hz), 2.87-3.64(m,10H),4.56(t,1H,J=5.9 Hz),4.77(d,1H,J=4.9 Hz),4.81(d,1H,J=4.4 Hz),4.91(d,1H,J=5.4 Hz),6.61(d,1H,J=2.0 Hz),6.20(d,1H,J=2.0 Hz),6.64(d,1H,J=8.8 Hz),7.00(d,2H,J=8.3 Hz),8.99(s,1H),9.32(s,1H),9.59(s,1H)

Reference 4 1-[2,4-Dihydroxy-6-{(β-D-glucopyranosyl)methyl}]acetophenone (Compound 61)

[0213]

[0214] According to similar procedure described in Example 44 step (c),the compound 61 was obtained from 1.5 g of1-[2,4-dihydroxy-6-[(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)methyl}]aceto-phenonein 57% yield (0.41 g). This compound was also used as a materials whensynthesized the compound 54. mp=227-228° C., [α]²³D=−12.00 (C=1.0, MeOH)

[0215] Mass (m/e,ESI): 351(M+Na)⁺,329(M+H)⁺

[0216] IR (cm⁻¹): 3394,1599,1455,1353,1269,1161,1083,1008,843,573

[0217]¹H-NMR (CDCl₃) δ: 2.47(s,3H),2.59(dABq,1H,J=14.7Hz),2.91-3.50(m,7H), 3.65(dABq,1H,J=11.7 Hz),4.25(bs,5H),6.18(d,1H,J=2.0Hz),6.27(d,1H, J=2.4 Hz),9.88(bs,1H)

Example 47 and 48

[0218] According to a similar procedure described in Example 44, thecompound 55 and 56 were synthesized via aldol reaction and catalytichydrogenation of double bond of enone derivatives, respectively.

Example 49

[0219] Instead of 5-benzofuranaldehyde,5-benzothiophenealdehyde wasreacted in a similar manner described in Example 44 step (b) followed bystep (c), to obtain the compound 57.

Example 50

[0220] According to a similar procedure described in Example 4, 5, and6, the compound 58 was synthesized via three steps that involveprotection of phenolic hydroxy groups, reaction of primary hydroxygroup, and removal of allyl group.

[0221] Effect of the Invention

[0222] A novel C-glycoside of this invention show Na⁺-glucosecotransporter inhibition activity, and it is stable to hydrolysis byβ-glucosidase and under the condition of acids and bases, and alsouseful for the agent of therapy/prophylaxis of diabetics andhypoglycemic agent.

What is claimed is
 1. A compound of the general formula (I),

wherein: with the provisos that R₁ is H, OH, lower alkyl, O-lower alkylor

R₂ is H, —COO-lower alkyl,

or

R₅ is —CH₂OH, —CH₂OCO₂-lower alkyl,

—CH₂OSO₃H, —COOH or —COONa; wherein: A is

(with the provisos that X is oxygen atom, nitrogen atom or sulfur atomR₃ is lower alkyl when is 1, R₃ is including —OH, —O-lower alkyl, . . .means saturated or unsaturated carbon bond; m is 0 or 1; n is 0, 1 or 2;above mentioned-lower alkyl means C₁-C₅.) or a pharmaceutical acceptablesalt.
 2. A process of the production of a compound of the generalformula (I)

wherein: R₄ is H, acetyl or benzyl group (in which R₁, m and n has theabove-mentioned meanings) General formula (II) is reacted with generalformula (IV): OHC—A₁ (in which A₁ has the above-mentioned meanings) byaldol condensation and following reduction, if desired.
 3. The treatmentand/or prevention agent of diabetes which is represented by generalformula (I) or its pharmaceutical acceptable salts.
 4. The blood glucoselowering agent which is represented by general formula (I) or itspharmaceutical acceptable salts.